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Tag: Infectious Diseases

  • Scientists identify distinct molecular signatures for sepsis diagnosis and prognosis

    Scientists identify distinct molecular signatures for sepsis diagnosis and prognosis

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    Researchers from Lund University in Sweden have identified distinct molecular signatures associated with the clinical signs of sepsis that could provide more accurate diagnosis and prognosis of sepsis, as well as help to target specific therapies at patients who would benefit most, according to new research being presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April).

    “A simple blood test when combined with a personalised risk model has the potential to save lives by providing more accurate sepsis diagnosis and determining who may go on to develop more severe clinical manifestations”, says co-lead author Dr Lisa Mellhammar from Lund University, Sweden. “It’s vital that patients with suspected sepsis are identified prior to the onset of organ failure. Given the challenges associated with timely diagnosis and the fact that sepsis kills millions of people around the world every year, there is an urgent demand for an alternative approach.”

    Sepsis is a life-threatening organ-dysfunction triggered by a severe infection. Severe sepsis and septic shock are progressive stages of sepsis, associated with multi-organ failure and death. According to WHO, there were an estimated 49 million sepsis cases and 11 million potentially preventable deaths in 2017-;accounting for almost 20% of all global deaths.

    One of the persistent challenges in treating sepsis is the lack of timely diagnosis, as there is no singular diagnostic test that reliably detects sepsis. Current practices rely on broad-ranged biomarkers such as CRP (C-reactive protein, an inflammation marker), PCT (procalcitonin, a pro-hormone), and lactate for the detection of sepsis.

    Additionally, sepsis is a highly variable disease that can arise from a multitude of causes, and despite hundreds of clinical trials there are no targeted treatments, and clinicians currently rely on the broad-spectrum use of antibiotic, antiviral, and antifungal therapies.

    It’s difficult to predict who will get sepsis, who will recover, and who will have poor outcomes. We urgently need better ways to understand sepsis at the molecular level so we can classify suspected sepsis patients according to the clinical manifestations of their illness and identify high-risk patients and develop more effective treatments.”


    Dr Adam Linder, co-lead author from Lund University, Sweden

    In this study, researchers set out to investigate the distinct proteomic signatures (unique patterns of proteins which are associated with immune response in patients with sepsis) associated with different clinical symptoms and outcomes, such as different organ dysfunctions and infections.

    They included 1,364 plasma samples from randomly selected adult patients with suspected sepsis admitted to the emergency department at Skåne University Hospital between 1st September 2016 and 31st of March 2023. Overall, 1,073/1,364 patients had an infection, and of these 913 had sepsis.

    The researchers used mass spectrometry to analyse the plasma samples and generate comprehensive molecular maps to better understand patterns of proteins that were predictive of septic shock. Each protein panel was then combined into a molecular signature to train a machine-learning model, allowing researchers to predict which patients would develop septic shock with high accuracy (see figure 1a in full abstract).

    Patients were then classified into low, medium, or high probability of developing septic shock and the model was able to show how increasing risk was associated with higher mortality (see figure 1b in full abstract).

    The researchers also identified panels of proteins that were predictive of six different types of organ dysfunction (cardio, central nervous system, coagulation, liver, kidney, and respiratory) and infection. They analysed the biological processes associated with each panel to show how their unique proteome signatures influence sepsis.

    Patients were then classified into five risk categories based on the probabilities of having organ dysfunctions and infection and the risk of dying.

    “A fast test that provides more accurate sepsis diagnosis and could also predict who is at greater risk of poorer outcomes now seems a genuine possibility”, says Mellhammar. “Any research like this needs clinical validation and many hurdles must be cleared before these biomarkers are used in the clinic. But we envision this as a tool that could be deployed worldwide, as the future of early detection of sepsis.”

    Despite the promising findings, the authors outline some limitations of their study, including that because sepsis is a highly variable disease, it is important that the findings are validated in different cohorts and settings. Additionally, because sepsis is a dynamic syndrome that progresses during the disease, repeated samples need to be taken from sepsis patients to study how the progress from earlier to later states affects the proteome. The authors also note that these data could benefit from further analysis, using for example, transcriptomics.

    Source:

    European Society of Clinical Microbiology and Infectious Diseases

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  • Higher COVID-19 hospitalization and mortality rates in MS patients despite vaccination

    Higher COVID-19 hospitalization and mortality rates in MS patients despite vaccination

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    New real-world research being presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April) reveals that people living with multiple sclerosis (MS) face a much higher risk of being hospitalized and dying from COVID-19 than the general population. The risk persists in individuals who received 3 or more vaccine doses.

    These findings indicate that vaccination alone may not adequately protect individuals with MS from severe COVID-19 outcomes, and underscore the urgent need for additional preventive measures against COVID-19 in this vulnerable population, say researchers.

    Having multiple sclerosis in itself doesn’t increase the risk of getting COVID-19, rather it’s the taking of immune modifying medicine such as B-cell depletion therapies that can reduce the effectiveness of vaccines by preventing the immune system from mounting a robust protective response. Some MS-specific factors, such as having underlying conditions or higher levels of disability can contribute to poor outcomes. As a result, even after repeated doses of COVID-19 vaccines, some individuals with MS remain at high risk of serious outcomes from COVID-19.”

    Professor Jennifer Quint, lead author from Imperial College London, UK

    The new analyses are part of the INFORM (INvestigation oF cOvid-19 Risk among iMmunocompromised populations) study, which analyzed data of nearly 12 million people aged 12 years and older in England to assess COVID-19’s impact, risk, and healthcare resource use (HCRU) among immunocompromised populations compared with the general population during the Omicron wave.

    Previous results from INFORM found that immunocompromised individuals face disproportionate burdens from COVID-19, with substantially higher risk of developing severe COVID-19 outcomes than the general population [1]. However, the specific burden faced by individuals with MS, which was not categorized as immunocompromised, was not assessed previously.

    To find out more, researchers compared the risk of COVID-19 hospitalization and death in vaccinated individuals with MS and the general population in England from 1st January to 31st December, 2022.

    They analyzed routinely collected, national primary and secondary care electronic data from a random sample of 25% of all individuals aged 12 years or older in England registered with the National Health Service (NHS). Subgroup analysis was conducted among individuals who had been vaccinated with three or more doses of COVID-19 vaccines by Jan 1st, 2022.

    Of 11,990,730 individuals included in the study, 16,350 (0.1%) individuals with MS were identified. Over half (6,060,635) of those in the general population and more than three-quarters (12,905) of patients with MS had been fully vaccinated (received at least three doses of a COVID-19 vaccine by Jan 1st, 2022).

    During the study, a total of 20,910 COVID-19 hospitalizations and 4,810 COVID-19 deaths were recorded in the general population, corresponding to crude overall incidence rates of 0.24 and 0.06 per 100 person-years, respectively.

    Among individuals with MS, there were 215 COVID-19 hospitalizations and 25 COVID-19 deaths, corresponding to substantially higher overall incidence rates of 1.28 and 0.14 per 100 person-years, respectively.

    After adjusting for age and sex, having MS was associated with a seven times greater risk of COVID-19 hospitalization and fourfold increased risk of dying from COVID-19 compared to the general population.

    “We hope that these findings raise awareness that the threat of COVID-19 is still very real for many, and that vaccine boosters are inadequate to protect this clinically vulnerable group”, says Professor Quint. “With new variants constantly emerging, people living with MS should be considered an important high-risk group for COVID-19 hospitalization and death for which additional preventive measures and multi-layered public health protections are urgently needed.”

    Despite the important findings, the authors point to several limitations, including that they can’t rule out the possibility that other unmeasured factors such as underling illness and level of MS disability might have influenced the results. They also note that they did not examine the effect of use of disease modifying therapies, time since last vaccination, type of vaccination, and prior infection.

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  • Managing the rise in STIs among older adults

    Managing the rise in STIs among older adults

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    A new research review presented at a pre-congress day for this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024, Barcelona, 27-30 April) will look at how to manage the rise in sexually transmitted infections (STIs) in older people, such as gonorrhea, syphilis, and genital warts. It will focus on the importance of sex, intimacy, and sexual health to the Baby Boomer generation, especially given that 1 in 6 individuals worldwide will be aged 60 and older by 2030. The presentation will be given by Professor Justyna Kowalska from the Medical University of Warsaw, Hospital for Infectious Diseases in Warsaw, Poland-;who will highlight the need for conversations around older people and sexual health to be normalized.

    Data from the US Centers for Disease Control and Prevention (CDC) indicate that rates of chlamydia, gonorrhea, and syphilis among US adults aged 55 and older have more than doubled over the past 10 years. For example, rates of gonorrhea among those aged 55 to 64 years rose from around 15 cases per 100,000 people in 2015 to 57 per 100,000 in 2019 [1]. In England, 31,902 new STIs were recorded in the over 45s in 2015, which rose to 37,692 in 2019 – an increase of 18%, with the majority of new diagnoses in men who have sex with men [2]. High STI prevalence estimates have also been reported more broadly in older adults around the world, including China, Korea, Kenya, and Botswana.

    Rising divorce rates, forgoing condoms as there is no risk of pregnancy, the availability of drugs for sexual dysfunction, the large number of older adults living together in retirement communities, and the increased use of dating apps are likely to have contributed to the growing incidence of STIs in the over 50s. These data likely underestimate the true extent of the problem as limited access to sexual health services for the over 50s, and trying to avoid the stigma and embarrassment both on the part of older people and healthcare professionals, is leading to this age group not seeking help for STIs.”


    Professor Justyna Kowalska from the Medical University of Warsaw

    Compounding the problem are the many misconceptions around sexuality and sexual activity in older adults, and the importance of sex and intimacy to older people’s happiness and wellbeing. As Professor Kowalska explains, “People do not become asexual with age. In fact, with preventive medicine and improved lifestyles people are enjoying a healthy life and sex life for longer. Older people often find greater satisfaction in their sex lives due to experience and known expectations. We need more role models like Samantha Jones in the TV show Sex and the City to challenge stereotypes around older sexuality.”

    Although the frequency of sexual activity tends to decline with age, older adults are still having lots of sex. In a study in England, half of men and almost a third of women aged 70 and over reported being sexually active. Similarly, in a Swedish study, 46% of individuals aged 60 years and older reported being sexually active, as did 10% of those aged 90 years or older.

    Studies show higher levels of sexual desire, greater sexual frequency, and more sexual partners among older men than women. A retrospective study from the USA involving 420,790 couples aged 67 to 99 years, found that widowhood was associated with an increased risk of STIs in older men, but not women. And the effects in men were larger after sildenafil (Viagra), the first phosphodiesterase type 5 inhibitor (PDE5 inhibitor), hit the market. Professor Kowalska says, “These findings indicate that sexual risk taking is common among older adults, particularly men. Given that the number of people aged 60 years and older is set to double worldwide by 2050 and the widespread availability of drugs to enhance sexual activity, health professionals must be proactive in discussing sexual concerns and making sexual health a routine part of general health care for older adults.”

    Although the incidence of STIs among the over 50s is small compared to younger age groups, it is rising, and Prof Kowalska will call for raising awareness about sexual health in older adults, explaining that they came of age at a time when sex education in school did not exist. “Sexual health campaigns are focused on young people and overlook the needs and experiences of those aged 50 and older”, she says. “Health promotion messages give the impression that condoms and concerns about STIs only apply to young people. But the dangers of undiagnosed and untreated STIs such as HPV-related cancers and onwards transmission are very real, particularly in this age group who are more likely to have underlying conditions such as heart disease and stroke.”

    Prof Kowalska will also highlight the lack of evidence for using communication to promote positive behaviors to reduce the spread of STIs in older adults, particularly outside the USA and for infections other than HIV. “Increasing older adults’ knowledge of the risk of STIs and how to engage in safer sex is crucial to tackling record levels of STIs”, says Professor Kowalska. “Tailoring education programs to the over 50s and including peer support and ensuring they are located within existing community settings is vital to their success.” Ultimately she says, “Older people have a right to good sexual health, so let’s normalize conversations around sex and older people, and change the narrative on aging.”

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  • Humans to animals transmission more common than previously thought

    Humans to animals transmission more common than previously thought

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    In a recent study published in Nature Ecology & Evolution, researchers harnessed publicly available viral genomic data, using a comprehensive suite of network and phylogenetic analyses to investigate the evolutionary mechanisms underpinning recent viral host jumps.

    Study: The evolutionary drivers and correlates of viral host jumps. Image Credit: Kateryna Kon/Shutterstock.comStudy: The evolutionary drivers and correlates of viral host jumps. Image Credit: Kateryna Kon/Shutterstock.com

    Background

    Viruses found in non-human vertebrates frequently cause infectious diseases, outbreaks, epidemics, and pandemics when they spread to individuals. Zoonotic host jumps, or the transmission of viruses from wild and domestic animal populations to people, have considerably impacted human health.

    Current knowledge is insufficient to forecast, prevent, and control future infectious disease concerns since only a tiny proportion of the viral variety has been defined, with surveillance studies lacking geographical and temporal coverage. Understanding the evolutionary processes underlying host leaps may help reduce these impacts.

    About the study

    In the present study, researchers analyzed 12 million sequenced viruses and host information provided by the National Center for Biotechnology Information (NCBI) to evaluate worldwide viral genomic monitoring.

    They identified overarching patterns in viral host jump directionality among humans and non-human vertebrate organisms and assessed observable adaptability associated with potential host jumps.

    The researchers investigated adaptive evolution signs in viral proteins that facilitate or maintain host leaps. They obtained information on all viral sequences available on NCBI Virus (n = 11,645,803) to determine the extent of acquired viral genomic information.

    The researchers then collected 58,657 quality-controlled viral genomes from NCBI Virus, covering 32 viral families and 62 vertebrate host orders, accounting for 24% of all vertebrate viral species.

    They used a species-agnostic network theory technique to identify viral cliques that are discrete taxonomic groupings with similar levels of genetic variation.

    The researchers found potential host jumps within these viral cliques using curated whole-genome alignments and maximum-likelihood phylogenetic reconstruction.

    They accounted for the most frequent directional selection measure at the genome level, i.e., the proportion of non-synonymous-type amino acid substitutions in each non-synonymous region (dN) to that of synonymous substitutions for every synonymous site (dS).

    The researchers investigated whether the intensity of selection associated with a host hop reduces for viruses with broad host ranges. They used a linear model to predict log10 (dN/dS) differences between host and non-host leaps and clique membership effects to estimate potential adaptation signals associated with lineages that have experienced host jumps for the various gene categories.

    The researchers expected that within each gene, adaptative alterations would be limited to functionally critical areas or subjected to significantly higher selective pressures from host immunity.

    Results

    The study found that individuals are both a source and a sink for viral spillover events, with more viral host transfers from humans to other species than from animals to humans.

    For viruses with greater host ranges, the level of adaptation associated with a host jump is smaller, with structural or auxiliary genes serving as primary selection targets. The work exposes considerable gaps in worldwide viral genomic animal surveillance, underscoring the need for meticulous sample metadata reporting.

    The bulk of viral sequences in NCBI (68%) were linked to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating extensive sequencing during the coronavirus disease 2019 (COVID-19).

    This collection contained 93% of vertebrate-related viral sequences, and most (93%) were associated with humans. The four viruses with the most sequenced genomes (Gallus, Sus, Anas, and Bos) were linked to domestic animals, and 15% of viral sequences were from vertebrates.

    User-uploaded host metadata for viral sequences remains inadequate, with 37% and 45% of viral genomic sequences from non-human hosts lacking related host information at the sample collection period and genus levels, respectively. The fraction of missing information varies significantly between virus families and nations.

    The researchers discovered 5,128 viral cliques spanning 32 viral families highly similar to ICTV-defined species. Despite the human-centric nature of genomic monitoring, viral cliques involving just animals account for 62% of all cliques, demonstrating the wide range of animal viruses in the worldwide viral-sharing network.

    The study showed that the minimal mutational distance for a putative host leap inside every viral clique was much higher than that of non-host jumps, showing that adaptation measurements were not biased.

    The observed host range for each viral clique was favorably correlated with higher sequencing intensity, indicating a significant positive relationship between the inter-host diversity of viral organisms and surveillance efforts.

    The intensity of adaptation signals differed by family, with structural proteins in coronaviruses showing the highest signals and auxiliary proteins in paramyxoviruses.

    Conclusion

    The study findings show that genomic data in the public domain helps understand viral host jumps, but there are gaps in understanding viral diversity. 81% of potential host jumps identified do not involve humans, highlighting the global viral-sharing network’s scale.

    Investigating the flow of viruses within this network could provide insights into managing infectious disease emergence at the human-animal interface. The study found that humans transmit more viral organisms to animals than humans, and multi-host virus-host jumps require fewer adaptations.

    The taxonomy-agnostic approach identified cliques consistent with traditional viral species nomenclature but also highlighted inconsistencies. Monitoring human-to-animal transmission of viruses is crucial for managing infectious diseases.

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  • Protection hinges on prior exposure

    Protection hinges on prior exposure

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    In a recent study published in the journal The Lancet Infectious Diseases, researchers conducted a prospective, longitudinal, population-based cohort study in two communities in the Philippines to investigate the effects of the prematurely discontinued CYD-TDV vaccine on children’s susceptibility to the dengue virus (DENV). While the first of three required doses of the vaccine was publicly administered in 2016 by the Philippine Department of Health, phase three CYD-TDV outcomes resulted in the vaccination program being discontinued.

    The present study reveals that the single administered dose of CYD-TDV was incapable of conferring protection against virologically confirmed dengue among patients without a prior history of DENV infection (zero or one prior infection). In stark contrast, young patients who had been exposed to two or more prior DENV infections were found to have substantially reduced DENV infection risk following the first CYD-TDV vaccine dose. This protection was found to be long-lasting, with the observed risk reduction persisting throughout the first three years and the subsequent follow-up period.

    Study: Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study. Image Credit: frank60 / ShutterstockStudy: Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study. Image Credit: frank60 / Shutterstock

    The dengue virus and the need for this study

    Dengue (DENV) is a mosquito-borne viral disease prevalent worldwide in tropical and subtropical regions, particularly in rural and underdeveloped communities. It can be caused by any of four closely related viruses (serotypes), given that repeat infections are surprisingly common. Disease severity can range from asymptomatic or mild to life-threatening, with common symptoms including high fever, persistent headaches, rashes, and characteristic muscle and joint pain.

    Despite years of research, dengue remains without a specific cure, with clinical interventions involving management of the fever and patient discomfort and pharmacotherapy restricted to common anti-viral drugs. Thankfully, numerous dengue vaccines have been developed and proven effective against the disease, saving countless lives, especially in recent decades. One of these vaccines developed in France in 2015 was the CYD-TDV vaccine, targeted at children and adolescents.

    “In 2015, a three-dose dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur, Lyon, France) was licensed in several dengue-endemic countries in people aged 9 years and older.”

    In 2016, the Philippine Department of Health undertook a vaccination drive for children in Calabarzon, Central Luzon, and Metro Manilla using CYD-TDV. Unfortunately, this drive was found to be premature – subsequent clinical trials revealed that DENV underperformed in younger children compared to their older counterparts (DENV seropositivity decreases with age). More importantly, the vaccine was found to be contraindicated in patients without a history of DENV infection. These outcomes resulted in the vaccination program’s termination following the administration of only the first CYD-TDV vaccine dose.

    Hitherto, however, the effect of that single vaccine dose on children’s disease resistance remains unexplored.

    About the study

    The present study aimed to evaluate the relative DENV infection risk among Cebu children who did or did not receive a single CYD-TVD dose, and the association of these outcomes with the number of previous DENV infections survived by these children. The study was designed as a prospective, longitudinal, population-based cohort study and comprised healthy children between the ages of nine and 14 years from Balamban municipality or Bogo city. The study protocol follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, with data collection carried out via a custom-designed questionnaire (demographic data collection) and 5 mL venous blood sample (for baseline DENV serostatus evaluation).

    Anthropometric and sociodemographic region data were additionally acquired from the Rural Health Units, which revealed that out of 285,242 eligible children, 149,023 had received the first CYYD-TVD dose. Enrolled participants were assigned to vaccine or no-vaccine cohorts based on these data sources, with follow-up blood and questionnaire collections 17-28 months following study initiation.

    “A participant with virologically confirmed dengue was defined as having acute febrile illness with a positive result by RT-PCR. We interviewed participants or the parent or guardian in hospital or at home in person or via telephone to establish the outcome of the illness. We classified cases of virologically confirmed dengue according to WHO criteria.”

    The study’s outcome of interest was the relative protection confirmed by the single vaccine dose, measured in terms of the number of subsequent infections following vaccination. Inter-cohort comparisons were statistically achieved using two-sample t tests (mean comparisons) and Wilcoxon rank-sum tests (median comparisons).

    Study findings

    Of the 3,087 children who volunteered for the study, 3,001 were found to meet the study inclusion criteria and were enrolled in the study. Of these, 2,778 provided completed demographic and medical data at both baseline and follow-up evaluations and were included in the final analyses.

    Serum sample assays revealed that 241 individuals (10.1%) were DENV naïve, of which 93 were unvaccinated. An overwhelming 1,906 participants (80.3%) were found to be DENV multitypic, indicating multiple infection cycles, potentially by different DENV serotypes.

    Analyses of subsequent DENV infection data highlight that the CYD-TDV dose was insufficient to protect naïve and monotypic profile patients from DENV infections, with no statistically discernible difference between individuals who had received the vaccine and those who had not. In contrast, patients with multitype DENV profiles who were then administered the vaccine dose displayed substantial, long-lasting improvements in their infection resistance. These results are surprising, as until recently, DENV monotypic patients were assumed to be at the highest infection risk due to the passive immunity of multitypic profile patients.

    “In summary, we found no protection from a single dose of CYD-TDV among children with a naive or monotypic DENV immune profile at baseline. One dose conferred significant protection against hospitalization for virologically confirmed dengue among children with a monotypic DENV immune profile at baseline. Since only one dose of CYD-TDV was given, the study cannot be used to inform public health decisions on vaccination but is relevant for children who receive an incomplete regimen.”

    Journal reference:

    • Ylade, M., Crisostomo, M. V., Daag, J. V., Agrupis, K. A., Cuachin, A. M., Sy, A. K., Kim, D. R., Ahn, H. S., Escoto, A. C., Katzelnick, L. C., Adams, C., White, L., de Silva, A. M., Deen, J., & Lopez, A. L. (2024). Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study. In The Lancet Infectious Diseases. Elsevier BV, DOI – 10.1016/s1473-3099(24)00099-9, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00099-9/fulltext

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  • Ubiquigent and Debiopharm enter agreement to support USP1 inhibitor programme for Debio 0432

    Ubiquigent and Debiopharm enter agreement to support USP1 inhibitor programme for Debio 0432

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    Ubiquigent Limited (Ubiquigent), a drug discovery and development company harnessing novel deubiquitinase (DUB) modulators as new therapeutics for areas of high unmet medical need, today announced an agreement with Debiopharm, a biopharmaceutical company aiming to develop tomorrow’s standard-of-care treatments to cure cancer and infectious diseases. The agreement will support the development of Debiopharm’s USP1 inhibitor programme, Debio 0432.

    Under the terms of the agreement, Ubiquigent will deploy its DUB-focused platform, combined with its deep understanding of the DUB field, to develop novel target engagement assays to support Debio-0432 as it approaches the clinic.

    Currently, in late-stage preclinical development, Debio 0432 is a small molecule with best-in-class potential that could be deployed to combat multiple tumour types. Through its potent and selective inhibition of USP1, a critical player in the DNA damage repair (DDR) pathway, Debio 0432 has the potential to induce synthetic lethality in tumour types with underlying defects of DNA repair genes.

    We are delighted to enter this agreement with Debiopharm, supporting the development of its advanced USP1 inhibitor programme. Following our successful collaborations with other clinical stage companies, this latest agreement further demonstrates the capability of Ubiquigent’s platform to address all aspects of DUB drug discovery and development, encompassing target validation, hit-to-lead, candidate selection, translational research, and the development of assays to support clinical evaluation.” Jason Mundin, CEO of Ubiquigent, said: “With multiple assets now reaching clinical stage, we look forward to seeing the continued progression and expansion of the DUB field over the coming years as more companies enter the space and new therapeutics enter the clinic.”

    Bertrand Ducrey, CEO, Debiopharm, commented: “Ubiquigent’s specialised drug discovery platform is uniquely positioned to support our USP1 inhibitor programme as it approaches the clinic, enabling the development of novel target engagement assays. Selective inhibition of USP1 to interrupt DNA damage repair pathway is an exciting approach to cancer treatment.”

    To learn more about Ubiquigent’s platform for DUB-focused drug discovery, visit: https://www.ubiquigent.com/platform

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  • Global fight against TB misses 2020 WHO milestones, despite progress in certain age groups

    Global fight against TB misses 2020 WHO milestones, despite progress in certain age groups

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    In a recent study published in The Lancet Infectious Diseases, researchers assessed the global, national, and regional burden and trends in tuberculosis.

    Study: Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021. Image Credit: SewCreamStudio/Shutterstock.comStudy: Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021. Image Credit: SewCreamStudio/Shutterstock.com

    Background

    Tuberculosis is a significant contributor to the global disease burden despite being a preventable and curable disease. It accounts for over a million deaths each year, and in 2019, it was the leading cause of death due to a single infectious agent. Global initiatives to address tuberculosis have been prominent since the 1990s.

    The World Health Organization (WHO) End TB Strategy aims to accelerate progress by reducing tuberculosis incidence and deaths by 90% and 95% between 2015 and 2035.

    Therefore, evaluations of the trends in the global tuberculosis burden are necessary to assess progress in achieving these targets.

    About the study

    In the present study, researchers examined the levels and trends in global tuberculosis burden and age-specific achievement of incidence and mortality milestones. They used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021.

    The team included data on vital registration, mortality surveillance, and minimally invasive tissue sample diagnoses for tuberculosis mortality in those without human immunodeficiency virus (HIV) coinfection.

    The cause-of-death ensemble modeling generated mortality estimates in those without HIV coinfection by age, sex, location, and year. Further, a population-attributable fraction approach was used to estimate age-specific deaths among those with HIV.

    In parallel, age-specific tuberculosis prevalence, incidence, and mortality were modeled using disease-model Bayesian meta-regression. Tuberculosis deaths attributable to risk factors were computed.

    Further, the impact of the coronavirus disease 2019 (COVID-19) pandemic on mortality was evaluated for countries with at least 10 tuberculosis deaths in 2019 for each age group.

    Tuberculosis incidence and mortality estimates were aggregated by HIV status, and all-form tuberculosis burden estimates were presented for five age groups – < 5, 5–14, 15–49, 50–69, and ≥ 70 years. Incidence- and mortality-specific annualized rates of change (ARCs) were reported.

    Findings

    Overall, 9.4 and 1.35 million tuberculosis cases and deaths occurred in 2021, respectively. Of these, tuberculosis and HIV coinfection cases accounted for a million cases and 205,000 deaths. The age-standardized incidence and mortality rates were 115 and 16.2 per 100,000 population, respectively. These rates declined by 37% and 61.1% between 1990 and 2021.

    In 2021, 3.8% of incident cases and 4.5% of deaths were reported in those under five years, and 4.7% of cases and 1.5% of deaths occurred in the 5–14 age group. Most cases (54.9%) and deaths (36.4%) in 2021 occurred in the 15–49 age group.

    In 2021, incidence rates exceeded 100 per 100,000 individuals in those aged five or younger across 34 countries and 5–14 across 14 countries.

    Further, incidence rates surpassed 500 per 100,000 individuals in the 15–49, 50–69, and ≥ 70 age groups in nine, 33, and 50 countries, respectively.

    Mortality rates were greater than 25 per 100,000 individuals in the < 5, 5–14, and 15–49 age groups in 20, 1, and 37 countries, respectively. Notably, mortality rates exceeding 300 per 100,000 individuals were observed in the 50–69 and ≥ 70 age groups in eight and 44 countries, respectively.

    ARCs in tuberculosis incidence were the largest in those aged <5 and 5–14 between 2020 and 2021, reducing by 4.1% and 3.7%, respectively, whereas reductions in adult age groups were around 2%.

    Moreover, the largest ARCs for mortality rates were observed in the same age groups. Central Asia and Central and Eastern Europe had the largest age-standardized ARCs between 2010 and 2021.

    Globally, all-age incidence rates reduced by 6.26% between 2015 and 2020, with a 4.9% decline in males and 7.9% in females. In the same period, global deaths due to tuberculosis declined by 11.9%, with a greater change in females (13.8%). Global tuberculosis deaths decreased to one million after removing the cumulative effects of risk factors (diabetes, smoking, and alcohol use).

    Forty-one countries were included in the analysis of the impact of COVID-19. Accordingly, 50,900 deaths due to tuberculosis were expected in 2020 compared to 45,500 deaths observed, corresponding to 5,340 fewer deaths than expected.

    Twenty countries continued to report data through 2021. In these countries, 39,600 deaths were expected compared to 39,000 observed.

    Conclusions

    The first WHO End TB interim milestones were not achieved in 2020, with only 6% and 12% reductions in incidence and mortality rates between 2015 and 2020, respectively.

    There was differential progress across age groups; people under 15 showed the sharpest decreases, whereas the older groups had minimal declines.

    The End TB incidence and mortality milestones were reached in 2020 by only 15 and 17 countries, respectively.

    As such, control programs should evaluate these countries to explore the drivers of their progress. Moreover, the impact of the COVID-19 pandemic was heterogeneous and uncertain, warranting additional data.

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  • UQ researchers use new dosing technology to enhance ICU antibiotic treatment

    UQ researchers use new dosing technology to enhance ICU antibiotic treatment

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    University of Queensland researchers have used dosing software to accelerate the effects of antibiotics in patients being treated for sepsis in Intensive Care Units.

    UQ researchers use new dosing technology to enhance ICU antibiotic treatment
    Dosing software improved antibiotic exposures in critically ill adults and children with sepsis. Image Credit: Adobe.

    Co-senior study author Professor Jason Roberts from UQ’s Centre for Clinical Research said the technique trialed in the DIRECT study meant patients received effective antibiotics in half the usual time, leading to faster recovery, higher quality care, cost savings and increased bed availability in the hospitals.

    “We found we could dramatically improve the accuracy and quality of the treatment provided to adults and children, meaning less time in the ICU and a faster cure,” Professor Roberts said.

    “We did this by rapidly identifying which bacteria was causing their severe infection, and then applying a personalized dosing approach to ensure each patient received the most effective dose for their needs.

    “The team used Bayesian dosing software in four adult and pediatric ICUs, leading to an estimated healthcare saving of $12,000 per patient in some groups.”

    The clinical trial was unusual because it included children and involved collaborators at four major Brisbane hospitals.

    UQCCR Principal Research Fellow and co-senior author Associate Professor Adam Irwin said improving the accuracy of infection treatment was a great outcome.

    “In this study, clinicians in pediatric and adult intensive care settings alike were confident to apply the dosing software recommendations, meaning critically ill children and adults will benefit from the results,” Dr Irwin said.

    We had ICU doctors and nurses, pharmacists, infectious diseases doctors, microbiologists and experts in health economics involved in the study.

    This research highlights our strong commitment to providing the best possible care for Queenslanders.

    We hope that further funding will allow us to demonstrate the value of this treatment approach to a broader international audience.”

    Professor Adam Irwin

    DIRECT was funded by MRFF Rapid Applied Research Translation Program Grants administered through Health Translation Queensland, and was conducted at the Herston Infectious Diseases Institute in collaboration with Metro North Health, Queensland Children’s Hospital and Metro South Health.

    The research is published in Intensive Care Medicine.

    Source:

    Journal reference:

    Chai, G.G., et al. (2024) Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis. Intensive Care Medicine. doi.org/10.1007/s00134-024-07353-3

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  • Southern expansion of hemorrhagic fever virus in Sweden linked to bank voles

    Southern expansion of hemorrhagic fever virus in Sweden linked to bank voles

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    Researchers have discovered that bank voles in Skåne, southern Sweden, carry a virus that can cause hemorrhagic fever in humans. This finding was made more than 500 km south of the previously known range. The virus strain discovered in Skåne appears to be more closely related to strains from Finland and Karelia than to the variants found in northern Sweden and Denmark. This is revealed in a new study from Uppsala University, conducted in collaboration with infectious diseases doctors in Kristianstad and published in the scientific journal Emerging Infectious Diseases.

    We were surprised that such high proportion of the relatively few voles that we caught were actually carrying a hantavirus that makes people ill. And this was in an area more than 500 km south of the previously known range of the virus.” 

    Elin Economou Lundeberg, infectious diseases doctor at Kristianstad Central Hospital, one of the study’s first authors

    Hantaviruses are a family of viruses naturally found mainly in rodents such as mice, rats and voles. Certain hantaviruses are able to infect people and cause two main groups of diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Both types of disease are notifiable under the Communicable Diseases Act, as they can cause serious problems and even death. In northern and central Europe, a variant of the virus, Puumala hantavirus, causes a relatively mild form of HRFS popularly known as ‘vole fever’ (nephropathia epidemica). However, studies have shown that this hantavirus can also cause very severe HRFS, which in the worst case can be fatal. In Sweden 100-450 cases of vole fever require hospital care each year, exclusively in the northern part of the country.

    In 2018, a locally contracted case of vole fever was reported in Skåne, more than 500 km south of the previously known southernmost incidence of the disease in Sweden, which was north of Uppsala. Another case was discovered in 2020, also in Skåne. In both cases, the patients concerned had not been away travelling and were infected in their home area. In an attempt to understand how this was possible, bank voles were caught in the vicinity of the patients’ homes and analysed for any occurrence of hantavirus. It turned out that 9 of the 74 bank voles caught carried hantavirus genes. Genetic studies have now shown that the virus differs markedly from the virus variants that circulate in northern Sweden and Denmark, and that it is most closely related to viruses from Finland and Karelia.

    The next step in the research is to find out where the virus comes from and map its distribution in the southern parts of Sweden.

    “If the virus has existed in the area for a long time and has simply not been discovered, why haven’t more people become ill? Or, has it become established in Skåne recently and only just begun to spread? And how did it get there?” wonders Professor Åke Lundkvist of Uppsala University, a co-author of the study. “Unfortunately the COVID-19 pandemic intervened, which considerably delayed the completion of this study. These findings are very interesting and show how important it is to investigate the causes as quickly as possible when we see an infectious disease in a new geographical area.”

    The study was financed by the EU (Horizon 2020) and SciLifeLab (Pandemic Laboratory Preparedness), along with local R&D funding from Kristianstad Central Hospital.

    Source:

    Journal reference:

    Ling, J., et al. (2024). Nephropathia Epidemica Caused by Puumala Virus in Bank Voles, Scania, Southern Sweden. Emerging Infectious Diseases. doi.org/10.3201/eid3004.231414.

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  • Boosting butyrate-producing gut bacteria lowers hospitalization rates for infections

    Boosting butyrate-producing gut bacteria lowers hospitalization rates for infections

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    A study of two large European patient cohorts has found that for every 10% increase in butyrate-producing bacteria in a patient’s gut, the risk of hospitalization for any infection falls by between 14 and 25% across two large national cohorts. The study will be presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April) and is by Robert Kullberg, Amsterdam University Medical Center, The Netherlands, and colleagues.

    Microbiota alterations are common in patients hospitalized for severe infections and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. These bacteria were investigated because they are commonly depleted in patients hospitalized for severe infections. Second, butyrate may have protective effects in several intestinal diseases (other than infections).

    However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. In this study, the authors investigated the relationship between baseline gut microbiota and the risk of future infection-related hospitalization in two large population-based cohorts – from the Netherlands (derivation; HELIUS) and Finland (validation; FINRISK 2002).

    Gut microbiota were characterized by sequencing the DNA of bacteria to identify the different types of bacteria present in fecal samples of the participants. The authors measured microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. The primary outcome was hospitalization or mortality due to any infectious disease during 5–7-year follow-up after fecal sample collection, based on national registry data. The authors then examined associations between microbiota and infection-risk using computer modelling. Further statistical modeling was used to adjust for variables including demographics, lifestyle, antibiotic exposure, and comorbidities.

    The researchers profiled gut microbiota from 10699 participants (4248 from The Netherlands and 6451 from Finland. A total of 602 participants (The Netherlands: n=152; Finland: n=450) were hospitalized or died due to infections (mainly community-acquired pneumonia) during follow-up.

    Gut microbiota composition of these hospitalized/deceased participants differed from those without hospitalization for infections. Specifically, each 10% higher abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalization for infections – 25% lower for participants from the Dutch cohort and 14% lower for the Finnish cohort. All types of infections were assessed together, not any one in particular. These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities.

    The authors say: “Gut microbiome composition, specifically colonization with butyrate-producing bacteria, is associated with protection against hospitalization for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections.”

    The authors say further analysis will be needed before trails in patients can begin. One of the challenges is the face are the butyrate-producing bacteria are strictly anaerobic (meaning they respire without using oxygen and cannot tolerate oxygen), which makes it very difficult to transport viable bacteria into the gut. Several research groups are working on addressing these challenges.

    Source:

    European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024)

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